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Antitumoral effect of maintained neutrophilia induced by rhG-CSF in a murine model of pancreatic cancer

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2019-02-27
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Springer Nature
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Although the protumoral functions of polymorphonuclear neutrophils are well known, some now-forgotten studies report antitumoral roles for these cells. The present work examines the antitumoral effect of maintained neutrophilia induced via the injection of recombinant human granulocyte colony stimulating factor (rhG-CSF, 100 μg/kg/day) in a Panc-1 subcutaneous xenograft murine model of pancreatic cancer. This treatment was compared with gemcitabine administration (120 mg/kg every two days) and a saline control (n = 6–7 mice per group). Compared to the controls, both the rhG-CSF- and gemcitabine-treated mice showed significantly suppressed tumor growth by day 4 (p < 0.001 and p = 0.013 respectively). From a mean starting volume of 106.9 ± 3.1 mm3 for all treatment groups, the final mean tumor volumes reached were 282.0 ± 30.7 mm3 for the rhG-CSF-treated mice, 202.6 ± 18.1 mm3 for the gemcitabine-treated mice and 519.4 ± 62.9 mm3 for the control mice (p < 0.004 and p < 0.01, respectively, vs. control). The rhG-CSF-treated tumors showed higher percentage necrosis than those treated with gemcitabine (37.4 ± 4.6 vs. 7.5 ± 3.0; p < 0.001). This is the first report of a clear anti-tumoral effect of rhG-CSF when used in monotherapy against pancreatic cancer. Since rhG-CSF administration is known to be associated with very few adverse events, it may offer an attractive alternative in the clinical treatment of pancreatic cancer.
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1. Schneider, G. & Schmid, R. M. Genetic alterations in pancreatic carcinoma. Mol Cancer. 2, 15 (2003). 2. Altwegg, R. et al. Second-line therapy for gemcitabine-pretreated advanced or metastatic pancreatic cancer. World J Gastroenterol. 18, 1357–64 (2012). 3. Huguet, F., Mukherjee, S. & Javle, M. Locally advanced pancreatic cancer: the role of definitive chemoradiotherapy. Clin Oncol (R Coll Radiol). 26, 560–568 (2014). 4. Balkwill, F. & Mantovani, A. Inflammation and Cancer: back to Virchow? The Lancet 357(9255), 539–545 (2001). 5. Souto, J. C., Vila, L. & Brú, A. Polymorphonuclear neutrophils and cancer: intense and sustained neutrophilia as a treatment against solid tumors. Med Res Rev 31, 311–363 (2011). 6. Brú, A., Albertos, S., López García-Asenjo, J. A. & Brú, I. Pinning of tumoral growth by enhancement of the immune response. Phys Rev Lett 92, 238101 (2004). 7. De Vree, W. J. A. et al. Evidence for an important role of neutrophils in the efficacy of photodynamic therapy in vivo. Cancer Res 56, 2908–2911 (1996). 8. Brú, A., Albertos, S., Subiza, J. L., López García-Asenjo, J. A. & Brú, I. The universal dynamics of tumor growth. Biophys J 85, 2948–2961 (2003). 9. Tamamori, Y. et al. Granulocyte-colony stimulating factor enhances chimeric antibody Nd2 dependent cytotoxicity against pancreatic cancer mediated by polymorphonuclear neutrophils. Int J Oncol 21, 649–654 (2002). 10. Linnebacher, M., Maletzki, C., Emmrich, J. & Kreikemeyer, B. Lysates of S. pyogenes serotype M49 induce pancreatic tumor growth delay by specific and unspecific antitumor immune responses. J Immunother 31, 704–713 (2008). 11. Maletzki, C., Linnebacher, M., Kreikemeyer, B. & Emmrich, J. Pancreatic cancer regression by intratumoral injection of live Streptococcus pyogenes in a syngenic mouse model. Gut 57, 483–491 (2008). 12. Hoshi, H. et al. MUC5AC protects pancreatic cancer cells from TRAIL-induced death pathways. Int J Oncol 42, 887–893 (2013). 13. Matsumoto, Y. et al. Recombinant human granulocyte colony-stimulating factor inhibits the metastasis of hematogenous and nonhematogenous tumors in mice. Int J Cancer 49, 444–449 (1991). 14. Kokura, S. et al. Role of polymorphonuclear leukocytes (PMN) and active oxygen species in hyperthermia-antitumoral effect of hyperthermia combined with rhG-CSF. Gan To Kagaku Ryoho 19, 1655–1658 (1992). 15. Siders, W. W. et al. Involvement of neutrophils and natural killer cells in the anti-tumor activity of alemtuzumab in xenograft tumor models. Leuk Lymphoma 51, 1293–1304 (2010). 16. Zivkovic, M. et al. Oxidative burst of neutrophils against melanoma B16-F10. Cancer Lett 246, 100–108 (2007). 17. Jaganjac, M., Poljak-Blazi, M., Zarkovic, K., Schaur, R. J. & Zarkovic, N. The involvement of granulocytes in spontaneous regression of Walker 256 carcinoma. Cancer Lett 260, 180–186 (2008). 18. Saint, F. et al. Leukocyturia as a predictor of tolerance and efficacy of intravesical BCG maintenance therapy for superficial bladder cancer. Urology 57, 617–622 (2001). 19. Siracusano, S. et al. The role of granulocytes following intravesical BCG prophylaxis. Eur Urol 51, 1589–1599 (2007). 20. Su, Y. B. et al. Double-blind, placebo-controlled, randomized trial of granulocyte-colony stimulating factor during postoperative radiotherapy for squamous head and neck cancer. Cancer J 12, 182–188 (2006). 21. Brú, A., Albertos, S., García-Hoz, F. & Brú, I. Regulation of neutrophilia by granulocyte colony stimulating factor: A new cancer therapy that reversed a case of terminal hepatocellular carcinoma. J Clin Res 8, 9–13 (2005). 22. Hay, E. D. Cell biology of extracellular matrix, Springer US, ISBN 978-1-4613-0881-2 (1981). 23. Kim, Y. et al. Induction of pulmonary neoplasia in the smoke-exposed ferret by 4-(methylnitrosamina)-1-(3-pyridyl)-1-butanone (NNK): A model for human lung cancer. Cancer Letters 234, 209–219 (2006). 24. Oettle, H., Stefan, P. & Neuhaus, P. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer. A randomized controlled trial. JAMA. 297(3), 267–277 (2007). 25. Bonilla, M. A. et al. Long-term safety treatment with recombinant human granulocyte colony-stimulating factor (r-methugG-CSF) in patients with severe congenital neutropenias. Br J Haematol 88, 723–730 (1994). 26. Céspedes, M. V. et al. Lurbinectedin induces depletion of tumor-associated macrophages, an essential component of its in vivo synergism with gemcitabine, in pancreatic adenocarcinoma mouse models. Dis Model Mech. 9, 1461–1471 (2016).
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